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CD74 Expression and Its Therapeutic Potential in Thyroid Carcinoma

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CD74 Expression and Its Therapeutic Potential in Thyroid Carcinoma S-P Cheng et al. CD74 in thyroid cancer 22:2 179–190 Research CD74 expression and its therapeutic potential in thyroid carcinoma Shih-Ping Cheng1,3,4, Chien-Liang Liu1,3, Ming-Jen Chen1,4,5, Ming-Nan Chien2,3, Ching-Hsiang Leung2,3, Chi-Hsin Lin5, Yi-Chiung Hsu6 and Jie-Jen Lee1,3,4 1Department of Surgery, 2Division of Endocrinology and Metabolism, Department of Medicine, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan 3Mackay Junior College of Medicine, Nursing, and Management, No. 92, Sheng-Ching Road, Peitou, Correspondence Taipei 11260, Taiwan should be addressed 4Department of Pharmacology, Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan to J-J Lee 5Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan Email 6Institute of Statistical Science, Academia Sinica, Taipei, Taiwan [email protected] Abstract CD74, the invariant chain of major histocompatibility complex class II, is also a receptor for Key Words macrophage migration inhibitory factor (MIF). CD74 and MIF have been associated with " CD74 tumor progression and metastasis in hematologic and solid tumors. In this study, we found " macrophage migration that 60 and 65% of papillary thyroid cancers were positive for CD74 and MIF inhibitory factor immunohistochemical staining respectively. Anaplastic thyroid cancer was negative for MIF, " thyroid cancer but mostly positive for CD74 expression. Normal thyroid tissue and follicular adenomas were " antibody negative for CD74 expression. CD74 expression in papillary thyroid cancer was associated with larger tumor size (PZ0.043), extrathyroidal invasion (PZ0.021), advanced TNM stage Endocrine-Related Cancer (PZ0.006), and higher MACIS score (PZ0.026). No clinicopathological parameter was associated with MIF expression. Treatment with anti-CD74 antibody in thyroid cancer cells inhibited cell growth, colony formation, cell migration and invasion, and vascular endothelial growth factor secretion. In contrast, treatment with recombinant MIF induced an increase in cell invasion. Anti-CD74 treatment reduced AKT phosphorylation and stimulated AMPK activation. Our findings suggest that CD74 overexpression in thyroid cancer is associated with advanced tumor stage and may serve as a therapeutic target. Endocrine-Related Cancer (2015) 22, 179–190 Introduction The majority of follicular cell-derived thyroid cancers is treatment of radioactive iodine-refractory differentiated differentiated carcinomas and can be treated successfully thyroid cancer. Further fundamental research is needed to with a combination of surgery and radioactive iodine discover new therapeutic targets with better effectiveness therapy. For patients with advanced thyroid cancer, whose and lower toxicity. disease progresses despite standard therapy, treatment CD74, also known as the invariant chain of major options are limited and survival is poor (Haugen & histocompatibility complex (MHC) class II, functions as Sherman 2013). Targeted therapies have begun receiving an MHC-II chaperone and participates in the trafficking of attention in recent years. Currently, the multikinase MHC-II molecules in antigen-presenting cells (Borghese & inhibitor sorafenib is the only targeted agent approved Clanchy 2011). It has been shown that CD74 might be by the US Food and Drug Administration for the expressed independently of MHC-II, and CD74 can bind http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-14-0269 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 10:54:17AM via free access Research S-P Cheng et al. CD74 in thyroid cancer 22:2 180 to non-MHC-II proteins (Ogrinc et al. 1993, Henne et al. consisted of 103 papillary carcinomas and five anaplastic 1995). Moreover, CD74 is a cell membrane receptor carcinomas. Of the 103 papillary carcinomas, ten showed for macrophage migration inhibitory factor (MIF), a a follicular structure and were diagnosed as follicular pleiotropic cytokine that has pro-inflammatory and variant of papillary carcinoma. Lymph node metastasis pro-tumorigenic properties (Leng et al.2003). This was present in 58 (56%) of 103 patients with papillary ligand–receptor interaction may be an important link thyroid cancer. Among these patients, metastatic lymph between chronic inflammation and carcinogenesis (Bucala nodes from 27 (47%) patients were included for the & Donnelly 2007). The expression of MIF and/or CD74 has immunohistochemical study. In addition, sections of five been explored in several forms of cancer (Ren et al. 2005, follicular adenomas and five samples from Graves’ disease Xu et al. 2008, Nagata et al. 2009, Cheng et al. 2011a). In were submitted to immunohistochemical analysis. addition, MIF has been identified as a hypoxia-induced For western blot analysis, total proteins were extracted gene, and its expression serves to activate a proangiogenic from eight paired samples of papillary thyroid cancer, four transcriptional program (Winner et al. 2007). paired samples of follicular adenoma, four samples from In autoimmune thyroid disease, MIF production in Hashimoto’s thyroiditis, and four from Graves’ disease. response to thyroid antigens, but not to control antigens, All were collected during surgery and immediately has been described (Lamki et al. 1973). Recently, using snap-frozen in liquid nitrogen. a nationwide population-based study, we reported an increased risk for the development of thyroid cancer after Cell culture and reagents a diagnosis of thyroiditis (Liu et al. 2014). Considering that MIF upregulation is associated with autoimmune thyroid Human papillary thyroid carcinoma cell lines BCPAP and disease and certain types of cancer, it is therefore K1 were purchased from the German Collection of interesting to investigate whether a differential expression Microorganisms and Cell Cultures (DSMZ, Braunschweig, of MIF and CD74 exists in thyroid cancer. Furthermore, Germany) and the European Collection of Cell Cultures the restricted expression of CD74 among normal tissues (ECACC, Salisbury, UK) respectively. Both have been and its rapid internalization make CD74 an attractive authenticated to be unique thyroid cancer cell lines therapeutic target for cancer therapy (Hansen et al. 1996). (Schweppe et al. 2008). The expression of thyroid-specific Milatuzumab, a humanized MAB that recognizes CD74, is genes is shown in Supplementary Figure S1, see section currently under investigation. In a phase 1 trial, mono- on supplementary data given at the end of this article. Endocrine-Related Cancer therapy with milatuzumab was able to stabilize advanced BCPAP harbored the homozygous mutation of BRAF, multiple myeloma (Kaufman et al. 2013). In this study, we whereas K1 had the heterozygous mutation. BCPAP cells evaluated the significance of MIF and CD74 expressions in were cultured at 37 8C in a humidified atmosphere of 5% thyroid cancer and the effects of anti-CD74 antibody on CO2 in RPMI 1640 medium (Gibco; Life Technologies) thyroid cancer cells. supplemented with 10% fetal bovine serum (FBS). K1 cells were cultured in DMEM (Gibco) mixed with Ham’s F12 (Sigma) and MCDB 105 (Sigma) medium in 2:1:1 Materials and methods proportions, supplemented with 10% FBS and 2 mM L-glutamine. Recombinant human MIF (#289-MF) was Patients and tissue samples purchased from R&D Systems (Minneapolis, MN, USA). This study was approved by the Institutional Review Board Anti-human CD74 antibody (specific for the extracellular (IRB) of MacKay Memorial Hospital (10MMHIS077). From domain of CD74, C-16; #sc-5438) was obtained from Santa January 2001 to November 2007, 334 patients underwent Cruz Biotechnology. thyroidectomy with therapeutic intent for newly diagnosed differentiated thyroid cancer at our institution. Cell viability and colony formation assay Incidental microcarcinomas were excluded. Eligible patients were de-identified and randomly selected for Cell growth was determined using the thiazolyl blue entry into the study. Each patient had complete clinical tetrazolium (MTT) bromide colorimetric assay. Briefly, and histopathological profile at diagnosis. Nonetheless, BCPAP and K1 cells (4000 cells/well) were seeded onto follow-up data were not available because of stringent 96-well plates and were allowed to grow in complete de-identification of patient records. Finally, a total of culture media for 24 h. Thereafter, the media was replaced 108 patients comprised our main study cohort. Lesions with culture media containing 1% FBS for a further http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-14-0269 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 10:54:17AM via free access Research S-P Cheng et al. CD74 in thyroid cancer 22:2 181 24–72 h. The cells were treated with isotype control, (Sysmex, Kobe, Japan), and counted under a light recombinant human MIF (200 ng/ml), or anti-CD74 microscope in five nonoverlapping fields. antibody (5 mg/ml). At the indicated time points, 100 ml (5 mg/ml) of MTT reagent (Sigma) was added to the cell Western blotting analysis culture and cells were incubated at 37 8C for 4 h. Formazan crystals converted from tetrazolium salts by viable cells Tissue or cellular proteins were extracted, quantified, and were solubilized with acidified isopropanol. The subjected to gel electrophoresis according to the standard absorbance was measured at 570 nm by a Varioskan procedures as we described previously (Cheng
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